Prognostic value of p53 protein expression for patients with gastric cancer – a multivariate analysis

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Mutations in the p53 gene, one of the most common genetic alterations in human cancer, are implicated in tumorigenesis and tumour progression. Although p53 protein expression appears to be correlated to prognosis in patients with malignancy, its prognostic role in gastric cancer has remained controversial. We examined the clinical significance of p53 overexpression in 427 patients with gastric cancer, using multivariate analysis. Tumour sections of gastric cancer tissues from these 427 Japanese patients were stained immunohistochemically with monoclonal antibody PAb1801. The presence of p53 expression was statistically compared with clinicopathological features and post-operative survival, using univariate and multivariate analyses. p53 expression was detected in 38.6% (165 out of 427) of these gastric cancers and immunoreactivity was not observed in normal mucosa adjacent to the tumour. A higher rate of p53 detection was observed among large tumours and in those with a prominent depth of invasion, lymphatic and vascular invasion and lymph node involvement. Prognosis was significantly worse for patients with p53-positive-staining tumours. The 5-year survival rate was 62.5% for patients with p53-negative tumours and 43.3% for those with positive malignancies. p53 expression was a significant prognostic factor for node-positive gastric cancers in subjects undergoing treatment with curative resection, as assessed by Cox regression analysis. Thus, the expression of p53 was closely related to the potential for tumour advance and a poorer post-operative prognosis for patients with gastric cancer.

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  1. Allred, D. C., Clark, G. M., Elledge, R., Fuqua, S. A. W., Brown, R. W., Chamness, G. C., Osborne, C. K. & McGuire, W. L. (1993). Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85: 200–206.

  2. Banks, L., Matlashewski, M. & Crawford, L. (1986). Isolation of human-p53-specific monoclonal antibodies and their use in the studies of human p53 expression. Eur J Biochem 159: 529–534.

  3. Bell, S. M., Scott, N., Cross, D., Sagar, P., Lewis, F. A., Blair, G. E., Taylor, G. R., Dixon, M. F. & Quirke, P. (1993). Prognostic value of p53 overexpression and c-Ki-ras gene mutations in colorectal cancer. Gastroenterology 104: 57–64.

  4. Bozzetti, F., Bonfanti, G., Bufalino, R., Menotti, V., Persann, S., Andreola, S., Doci, R. & Gennari, L. (1982). Adequacy of margins of resection in gastrectomy for cancer. Ann Surg 196: 685–690.

  5. Brambilla, E., Gazzeri, S., Moro, D., de Fromentel, C. C., Gouyer, V., Jacrot, M. & Brambilla, C. (1993). Immunohistochemical study of p53 in human lung carcinomas. Am J Pathol 143: 199–210.

  6. Caelles, C., Helmberg, A. & Karin, M. (1994). p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370: 220–223.

  7. Carson, D. A. & Lois, A. (1995). Cancer progression and p53. Lancet 346: 1009–1011.

  8. Chang, F., Syrjänen, S. & Syrjänen, K. (1995). Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13: 1009–1022.

  9. Chin, K-V, Ueda, K., Pastan, I. & Gottesman, M. H. (1992). Modulation of activity of the promoter of the human MDR1 gene by ras and p53. Science 255: 459–462.

  10. Cox, D. R. (1972). Regression models and life tables. J R Stat Soc Series B 34: 187–220.

  11. Cross, S. M., Sanchez, C. A., Morgan, C. A., Schimke, M. K., Ramel, S., Idzerda, R. L., Raskind, W. H. & Reid, B. J. A. (1995). A p53-dependent mouse spindle checkpoint. Science 267: 1353–1356.

  12. Dixon, W. J. (1988). BMDP Statistical Software, University of California Press: Berkeley, CA

  13. Elledge, R. M., Gray, R., Mansour, E., Yu, Y., Clark, G. M., Ravdin, P., Osborne, C. K., Gilchrist, K., Davidson, N. E., Robert, N., Tormey, D. C. & Allred, D. C. (1995). Accumulation of p53 protein as a possible predictor of response to adjuvant combination chemotherapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone for breast cancer. J Natl Cancer Inst 87: 1254–1256.

  14. Finlay, C. A., Hinds, P. W., Tan, T-H, Eliyahu, D., Oren, M. & Levine, A. J. (1988). Activating mutations for transformation by p53 produce a gene product that forms an hsc 70–p53 complex with an altered half-life. Mol Cell Biol 8: 531–539.

  15. Furihata, M., Ohtsuki, Y., Sonobe, H., Shuin, T., Yamamoto, A., Terao, N. & Kuwahara, M. (1988). Prognostic significance of cyclin E and p53 protein overexpression in carcinoma of the renal pelvic and ureter. Br J Cancer 77: 783–788.

  16. Gabbert, H. E., Müller, W., Schneiders, A., Meier, S. & Hommel, G. (1995). The relationship of p53 expression to the prognosis of 418 patients with gastric carcinoma. Cancer 76: 720–726.

  17. Gannon, J. V., Greaves, R., Iggo, R. & Lane, D. P. (1990). Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J 9: 1595–1602.

  18. Govender, D., Harilal, P., Hadley, G. P. & Chetty, R. (1998). p53 protein expression in nephroblastomas: a predictor of poor prognosis. Br J Cancer 77: 314–318.

  19. Harris, C. C. & Hollstein, M. (1993). Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329: 1318–1327.

  20. Japanese Research Society for Gastric Cancer (1981). The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg 11: 127–139, Part II. Histological classification of gastric cancer. Jpn J Surg 11: 140–145

  21. Japanese Research Society for Gastric Cancer(ed) (1993). The General Rules for Gastric Cancer Study, (in Japanese), 12th edn. Kanehara and Co.: Tokyo, Japan

  22. Joypaul, B. V., Hopwood, D., Newman, E. L., Qureshi, S., Grant, A., Ogston, S. A., Lane, D. P. & Cuschieri, A. (1994). The prognostic significance of the accumulation of p53 tumour-suppressor gene protein in gastric adenocarcinoma. Br J Cancer 69: 943–946.

  23. Kakeji, Y., Korenaga, D., Tsujitani, S., Baba, H., Anai, H., Maehara, Y. & Sugimachi, K. (1993). Gastric cancer with p53 overexpression has high potential for metastasising to lymph nodes. Br J Cancer 67: 589–593.

  24. Kang, S-M, Maeda, K., Onoda, N., Chung, Y-S, Nakata, B., Nishiguchi, Y. & Sowa, M. (1997). Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer 74: 502–507.

  25. Kawasaki, S. (1975). A clinicopathological study on upward intramural extension of cancer of the stomach (in Japanese with English abstract). Fukuoka Acta Med 66: 1–23.

  26. Kim, J-H, Takahashi, T., Chiba, I., Park, J-G, Birrer, M. J., Roh, J. K., Lee, H. D., Kim, J-P, Minna, J. D. & Gazdar, A. F. (1991). Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst 83: 938–943.

  27. Koechli, O. R., Schaer, G. N., Seifert, B., Hornung, R., Haller, U., Eppenberger, U. & Mueller, H. (1994). Mutant p53 protein associated with chemosensitivity in breast cancer specimens. Lancet 344: 1647–1648.

  28. Korenaga, D., Okamura, T., Baba, H., Saito, A. & Sugimachi, K. (1988). Results of resection of gastric cancer extending to adjacent organs. Br J Surg 75: 12–15.

  29. Levine, A. J., Momand, J. & Finlay, C. A. (1991). The p53 tumour suppressor gene. Nature 351: 453–456.

  30. Levine, A. J., Perry, M. E., Chang, A., Silver, A., Dittmer, D., Wu, M. & Welsh, D. (1994). The 1993 Walter Hubert Lecture: The role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 69: 409–416.

  31. Lowe, S. W., Bodis, S., McClatchey, A., Remington, L., Ruley, H. E., Fisher, D. E., Housman, D. E. & Jacks, T. (1994). p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810.

  32. Maehara, Y., Okuyama, T., Moriguchi, S., Orita, H., Kusumoto, H., Korenaga, D. & Sugimachi, K. (1992a). Prophylactic lymph node dissection in patients with advanced gastric cancer promotes increased survival time. Cancer 70: 392–395.

  33. Maehara, Y., Orita, H., Okuyama, T., Moriguchi, S., Tsujitani, S., Korenaga, D. & Sugimachi, K. (1992b). Predictors of lymph node metastasis in early gastric cancer. Br J Surg 79: 245–247.

  34. Maehara, Y., Okuyama, T., Oshiro, T., Baba, H., Anai, H., Akazawa, K. & Sugimachi, K. (1993). Early carcinoma of the stomach. Surg Gynecol Obstet 177: 593–597.

  35. Maehara, Y., Okuyama, T., Kakeji, Y., Endo, K., Yamamoto, M. & Sugimachi, K. (1995). A tumour-associated cell-surface glycoprotein accompanying p53 overexpression and higher growth potential for gastric cancer. Br J Cancer 71: 999–1002.

  36. Martin, H. M., Filipe, M. I., Morris, R. W., Lane, D. P. & Silvestre, F. (1992). p53 expression and prognosis in gastric carcinoma. Int J Cancer 50: 859–862.

  37. McLaren, R., Kuzu, I., Dunnill, M., Harris, A., Lane, D. & Gatter, K. C. (1992). The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer 66: 735–738.

  38. Mönig, S. P., Eidt, S., Zirbes, T. K., Stippel, D., Baldus, S. E. & Pichlmaier, H. (1997). p53 expression in gastric cancer. Clinicopathological correlation and prognostic significance. Dig Dis Sci 42: 2463–2467.

  39. Motojima, K., Furui, J., Kohara, N., Ito, T. & Kanematsu, T. (1994). Expression of p53 protein in gastric carcinomas is not independently prognostic. Surgery 116: 890–895.

  40. Narayana, A., Vaughan, A. T. M., Gunaratne, S., Kathuria, S., Walter, S. A. & Reddy, S. P. (1998). Is p53 an independent prognostic factor in patients with laryngeal carcinoma? Cancer 82: 286–291.

  41. Oiwa, H., Maehara, Y., Ohno, S., Sakaguchi, Y., Ichiyoshi, Y. & Sugimachi, K. (1995). Growth pattern and p53 overexpression in patients with early gastric cancer. Cancer 75: 1454–1459.

  42. Piffkò, J., Bànkfalvi, À, Tory, K., Füzesi, L., Bryne, M., Öfner, D., Kusch, F., Joos, U. & Schmid, K. W. (1998). Molecular assessment of p53 abnormalities at the invasive front of oral squamous cell carcinomas. Head Neck 20: 8–15.

  43. Porter, P. L., Gown, A. M., Kramp, S. G. & Coltrerea, M. D. (1992). Widespread p53 overexpression in human malignant tumors. Am J Pathol 140: 145–153.

  44. Quinlan, D. C., Davidson, A. G., Summers, C. L., Warden, H. E. & Doshi, H. M. (1992). Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res 52: 4828–4831.

  45. Sakaguchi, T., Watanabe, A., Sawada, H., Yamada, Y., Yamashita, J., Matsuda, M., Nakajima, M., Miwa, T., Hirao, T. & Nakano, H. (1998). Prognostic value of cyclin E and p53 expression in gastric carcinoma. Cancer 82: 1238–1243.

  46. Sarbia, M., Porschen, R., Borchard, F., Horstmann, O., Willers, R. & Gabbert, H. E. (1994). p53 protein expression and prognosis in squamous cell carcinoma of the esophagus. Cancer 74: 2218–2223.

  47. Schneider, B. G., Hilsenbeck, S. G., Hensel, C. H., Pekkel, V., Shelton, C. H., Rodríguez-Martínez, H. A., Gutiérrez-Díaz, C. M. E., Pulitzer, D. R. & Allred, D. C. (1994). p53 mutations in gastric and colorectal cancers in Texas Hispanics versus Anglos. Virchows Arch 424: 187–193.

  48. Shimaya, K., Shiozaki, H., Inoue, M., Tahara, H., Monden, T., Shimano, T. & Mori, T. (1993). Significance of p53 expression as prognostic factor in oesophageal squamous cell carcinoma. Virchows Arch A Pathol Anat 422: 271–276.

  49. Sobin, L. H. & Wittekind, C. (1997). TNM Classification of Malignant Tumour, 5th edn. John Wiley & Sons: New York, NY

  50. Soussi, T., Legros, Y., Lubin, R., Ory, K. & Schlichtholz, B. (1994). Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 57: 1–9.

  51. Starzynska, T., Bromley, M., Ghosh, A. & Stern, P. L. (1992). Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 66: 558–562.

  52. Sugimachi, K., Maehara, Y., Ogawa, M., Kakegawa, T. & Tomita, M. (1997). Dose intensity of uracil and tegafur in postoperative chemotherapy for patients with poorly differentiated gastric cancer. Cancer Chemother Pharmacol 40: 233–238.

  53. Suto, T., Sugai, T., Nakamura, S., Funato, O., Nitta, H., Sasaki, R., Kanno, S. & Saito, K. (1998). Assessment of the expression of p53, MIB-1 (Ki-67 antigen), and argyrophilic nucleolar organizer regions in carcinoma of the extrahepatic bile duct. Cancer 82: 86–95.

  54. Takahashi, Y., Bucana, C. D., Cleary, K. R. & Ellis, L. M. (1998). p53, vessel count, and vascular endothelial growth factor expression in human colon cancer. Int J Cancer 79: 34–38.

  55. Thor, A. D., Moore, IIDH, Edgerton, S. M., Kawasaki, E. S., Reihsaus, E., Lynch, H. T., Marcus, J. N., Schwartz, L., Chen, L-C, Mayall, B. H. & Smith, H. S. (1992). Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84: 845–855.

  56. Uchino, S., Noguchi, M., Ochiai, A., Saito, T., Kobayashi, M. & Hirohashi, S. (1993). p53 mutation in gastric cancer: a genetic model for carcinogenesis is common to gastric and colorectal cancer. Int J Cancer 54: 759–764.

  57. Vogelstein, B. & Kinzler, K. W. (1992). p53 function and dysfunction. Cell 70: 523–526.

  58. Wynford-Thomas, D. (1992). p53 in tumour pathology: can we trust immunocytochemistry? J Pathol 166: 329–330.

  59. Yamaguchi, A., Nakagawara, G., Kurosaka, Y., Nishimura, G., Yonemura, Y. & Miyazaki, I. (1993). p53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance. Br J Cancer 68: 399–402.

  60. Yokozaki, H., Kuniyasu, H., Kitadai, Y., Nishimura, K., Todo, H., Ayhan, A., Yasui, W., Ito, H. & Tahara, E. (1992). p53 point mutations in primary gastric carcinomas. J Cancer Res Clin Oncol 119: 67–70.

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Maehara, Y., Tomoda, M., Hasuda, S. et al. Prognostic value of p53 protein expression for patients with gastric cancer – a multivariate analysis. Br J Cancer 79, 1255–1261 (1999) doi:10.1038/sj.bjc.6690201

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  • gastric cancer
  • p53 expression
  • prognosis
  • multivariate analysis

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